Successful transplantation requires a delicate balance of immunosuppression, enough to combat host graft rejection and graft vs host disease without leaving the host vulnerable to infections. This balance is difficult to achieve in practice, because one cannot always identify HLA-identical donars. Therefore, the ultimate goal of clinical transplantation must be to achieve donor specific tolerance. Total lymphoid irradiation may emerge as one of the few treatment strategies that truly induces immunologic tolerance. TLI is commonly used for HLA-identical bone marrow transplantation, but its clinical use in allogeneic transplants is still under investigation. Part of the difficulty in moving TLI into the allogeneic transplantation rests with the timing of TLI and the concurrent use of immunosuppressives. Understanding the mechanism of how TLI induces and maintains tolerance in allogeneic transplantation models will help to overcome some of these problems. TLI therapy may induce and maintain tolerance by immunoredirecting alloreactivity toward Th2 responses. This hypothesis has profound significance to clinical transplantation, because heavy immunosupression may block the Th2 immunoregulatory mechanisms that allow tolerance. The present proposal focuses on how immunoredirection (i.e., the enhanced Th2 CD4 alloreactivity) functions to maintain tolerance in the TLI mouse model. Aims I and II investigate the hypotheses that tolerogenic Th2 CD4 cells mediate tolerance in vivo by promoting the maturation of naive CD4 cells to alloreactive Th2 CD4 cells and prohibiting maturation of the Th1 cells, using adoptive transfer experiments. Aim III examines the hypothesis that tolerogenic Th2 CD4 cells regulate antigen presenting cell function by decreasing B7-1 expression and IL-12 production. Aim IV tests the novel hypothesis of linked tolerance which proposes that tolerance in the TLI model can spread to other antigenic determinants that are expressed on the APC. The results may renew the transplant communitys interest in pursuing TLI as an important adjunct therapy in allogeneic transplantation.